Abstract Type 2 Diabetes is recognized as an important risk factor for more severe and progressive periodontitis. Diabetic condition may accelerate periodontitis through metabolic dysregulation, shift in bacterial colonization, inflammation, and bone loss. We recently found that succinate activates succinate receptor (SucnR1) to stimulate osteoclastogenesis and bone resorption. Our preliminary data further show (1) succinate was elevated in the gingival crevicular fluid (GCF) from periodontitis patients and the elevation was significantly greater in patients with both periodontitis and T2D; (2) spontaneous periodontitis in T2D mice was accompanied by elevated succinate levels in the periodontium and altered gastrointestinal microbiome compare to normal mice; (3) succinate favors the growth of periodontal pathogens in vitro; (4) exogenous succinate enhances periodontal bone loss in wild type (WT); and (5) the periodontal bone loss is mitigated in SucnR1 knock out mice (KO) mice. The current proposal is built on strong preliminary data to determine whether succinate elevation accelerates periodontal disease progression. We will employ mouse models to test our hypotheses that targeting succinate signaling prevents accelerated periodontal disease pathogenesis. In Aim 1 we will use mice fed on normal diet, mice fed on High Fat Diet (HFD) which become hyperglycemic, and succinate receptor knock out mice (SucnR1_KO) to determine whether succinate/SucnR1 signaling influences systemic response and alters oral microbiota in normal and hyperglycemia conditions. We will use bacterial transfer from the periodontal site to germ free mice to test the pathogenicity as measured by bacteria-induced bone loss. Our working hypothesis is bacteria from HFD diabetic mice will induce more bone loss than bacteria from matched normoglycemic controls. In Aim 2 we will determine whether succinate activates SucnR1 to enhance periodontal bone loss stimulated by inflammation stimulus. In Aim 3 we will determine whether blocking succinate signaling in pre-osteoclasts alleviates periodontium bone loss. We will use lysMCre, SucnR1L/L mouse model to assess whether succinate signaling through its receptor to enhance non-inflammatory stimuli induced bone loss. We will also test the efficacy of a specific SucnR1 antagonist in preventing periodontitis in a T2D mouse model that spontaneously develop periodontitis. We propose that via activation of SucnR1, succinate has significant implications in periodontal disease and by delineating this novel mechanism, we will help to prevent periodontal bone loss in diabetic patients.